EP1453819A2 - Composes de type statine - Google Patents

Composes de type statine

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Publication number
EP1453819A2
EP1453819A2 EP02781169A EP02781169A EP1453819A2 EP 1453819 A2 EP1453819 A2 EP 1453819A2 EP 02781169 A EP02781169 A EP 02781169A EP 02781169 A EP02781169 A EP 02781169A EP 1453819 A2 EP1453819 A2 EP 1453819A2
Authority
EP
European Patent Office
Prior art keywords
compound
compounds
cbs
isolated
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02781169A
Other languages
German (de)
English (en)
Inventor
Jens Christian Frisvad
Lene Lange
Kirk Schnorr
Steen Stender
Thomas Ostenfeld Larsen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MycoTeQ AS
Original Assignee
Kobenhavns Amt
Novozymes AS
Danmarks Tekniskie Universitet
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kobenhavns Amt, Novozymes AS, Danmarks Tekniskie Universitet filed Critical Kobenhavns Amt
Publication of EP1453819A2 publication Critical patent/EP1453819A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to compounds with structures resembling natural statins isolated from Penicillium spp.
  • the present invention relates to isolated compounds having UV max relative absorbance spectra as measured by HPLC-DAD, of 222-224 nm (100 %), 229-234 nm shoulder (84-89 %), 290 nm shoulder (13 %), 303-305 nm (14-15 %), 318-320 nm shoulder (9-11 %), 331-333 nm (7.5-8.5%).
  • Another aspect of the present invention relates to a pharmaceutical composition comprising the compounds of the invention and the use of the compounds as a medicament.
  • Still another aspect of the invention relates to a method for the production of a compound of the inventention.
  • an aspect of the invention relates to a method of reducing the level of low-density lipoprotein cholesterol in a human or animal.
  • a further aspect relates to a method of producing a compound of the invention.
  • the isolated compounds can be used in therapy for treatment of hypercholesterolemia or osteoporosis or as precursors for lead compounds with therapeutic effect.
  • statins comprise natural products (polyketides) from fungi that have a series of strong effects on some of the most important human diseases.
  • Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR).
  • HMGR is the enzyme responsible for catalyzing the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the cholesterol biosynthetic pathway.
  • Statins are effective lipid lowering agents and thus have been widely used for lowering serum cholesterol levels in the treatment of hypercholesterolemia reducing the risk of heart attacks.
  • Statins also promote bone formation by affecting the expression of the bone morphogenic protein-2 (BMP- 2) and this stimulation can have beneficial effects for the treatment of bone fractures and osteoporosis (Mundy et al., Science(1999) 286: 1946-1949 ; Sugiyama et al., Biochem Biophys Res Commun (2000) 271 :688-92).
  • statins have recently also been recognized as a new type of immunomodulator by acting as direct inhibitors of induction of MHC-II expression by INF- ⁇ and thus as repressors of MHC-ll-mediated T-cell activation (Kwark et al., Nature Med., (2001 ) 6: 1399-1402).
  • Naturally occurring statins have antifungal activity (Auclair et al., Bioorganic and Medicinal Chemistry Letters (2001 ), 11 : 1527-1531 ).
  • Chemically modified statin molecules vary in their retention time in the body, the area of accumulation in the body and effectiveness per dose among other differences (Motti et al., Ann Ital Med Int, 2000, 15: 96-102).
  • mevinolins are produced by Aspergillus terreus and Monascus ruber, while Endo et al. (Journal Antibiotics, (1976), 29: 1346-1348) reports the production of compactins by Penicillium citrinum.
  • statins Due to pleiotropic effects of statins, their reported side effects (gastrointestinal disorders, skin rashes and headache (US 6,245,800)), and the variation in retention time in the body, and effectiveness per dose, a need still exists for statin molecules with unique and desirable properties such as increased effectiveness, less toxicity, altered retention time or concentration in a particular organ compared to commercially available statins.
  • the present invention relates to isolated compounds having UV max relative absorbance spectra as measured by HPLC-DAD, of 222-224 nm (100 %), 229-234 nm shoulder (84-89 %), 290 nm shoulder (13 %), 303-305 nm (14-15 %), 318-320 nm shoulder (9- 11 %), 331-333 nm (7.5-8.5%), and UV min relative absorbance spectra as measured by HPLC-DAD at 202-204 nm (26-45 %), 254-258 nm (2-3 %), 326-328 nm (6-8 %).
  • the present invention relates to a compound of formula (IV),
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the compounds(s) according to the invention or solistatin or a pharmaceutically acceptable salt or metabolite or prodrug thereof, and a pharmaceutical acceptable carrier.
  • the present invention relates to a use of the compound(s) according to the invention or solistatin for the production of a medicament.
  • the present invention relates to a use of the compound(s) of the invention or solistatin as a medicament.
  • the present invention relates to a use of the compound(s) of the invention for the manufacture of a medicament for the treatment of hypercholesterolemia and/or osteoporosis, or for use as an immunosuppessor.
  • the present invention relates to a method of reducing the level of low-density lipoprotein cholesterol (LDL-C) in a human or animal by administering an effective amount of at least one compound according to the invention or solistatin.
  • LDL-C low-density lipoprotein cholesterol
  • the present invention relates to a method of producing a compound of the invention, which method comprises a) culturing a organism in a suitable culture medium under conditions promoting the production of the said compound(s); and b) recovering the compound(s) from the organism or culture medium obtained in step (a).
  • Figure 1 shows UV-absorbance spectra as measured by HPLC-DAD for the Statans A, A ⁇ and B.
  • Figure 2 shows the development in total plasma cholesteol (avarege) of Statan A in rabbits.
  • statin any inhibitor of 3- hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), wherein a HMG-like moiety (present in all known statins) of the statin competes for binding at the active site of the HMG-reductase, with the HMG-moiety of HMG-CoA.
  • HMGR 3- hydroxy-3-methylglutaryl coenzyme A reductase
  • Solistatin is a compound of formula (I) , wherein Ri is H; R 2-4 is H; R 5 is H, and X is a compound of formula (II).
  • Retention index The retention index or bracketed retention index is based on a series of alkylphenone standards (acetophenone, propiophenone, butyrophenone, valerophenone, hexanophenone, octanophenone and decanophenone) run before each series of HPLC runs.
  • Acetophenone has the RI value 800 (because there are 8 carbon atoms in the molecule), propiophenone is 900 (9 carbon atoms) etc.
  • the Rl value is calculated by linear interpolation (see formula in Frisvad and Thrane, J. Chromatogr.(1987) 404:195-214).
  • HPLC-DAD High performance liquid chromatography with diode array detection (UV detector). UV absorbance of the compound is measured at different (a spectrum) wavelengths simultaneously.
  • the mevinolins only include one or two double-bonds (the latter a transoid conjugated diene) in the naphthyl part of the molecules giving either uncharacteristic end-absorbtions or the characteristic UV spectrum of the main 1 ,2,6,7,8,8a-hexahydronaphthyl group (absorbtions at 231 , 238 and 247 nm, see figure 1 in Endo, J. Antibiotics (1979),32: 852-854).
  • This characteristic chromophore has only been found in the naturally occurring statins and in versiol (LL-N313epsilon).
  • Mevinolin is always the main statin in the mevinolin secondary metabolite biosynthetic family and compactin is always the main statin in the compactin secondary metabolite biosynthetic family and at least one of them should be present in an extract in order to claim that statins are produced by an organism.
  • statans compounds comprising a chromophore different both from the characteristic chromophore of the 1 ,2,6,8,8a-hexahydronaphthyl group present in both compactin and mevinolin and the naphthyl group of solistatin as evidenced by UV-spectral data.
  • Said chromophore is different from known secondary metabolites, but has a resemblance to the chromophore of 8-methoxy-1-naphthol (see Stadler, M.
  • statans chromophore comprised in the compounds of the invention (the statans) and isolated from statin producing isolates of P. solitum can be characterized by their unique UV-spectra.
  • the present invention therefore relates to isolated compounds having UV max relative absorbance spectra as measured by HPLC-DAD, of 222-224 nm (100 %), 229-234 nm shoulder (84-89 %), 290 nm shoulder (13 %), 303-305 nm (14-15 %), 318-320 nm shoulder (9-11 %), 331-333 nm (7.5-8.5%), and UV min relative absorbance spectra as measured by HPLC-DAD at 202-204 nm (26-45 %), 254-258 nm (2-3 %), 326-328 nm (6-8 %).
  • the isolated compounds characterized by the above UV-spectra also shown in Fig.
  • the isolated compounds according to the present invention should according to the observed spectra above have structures resembling the naturally occurring statins known as compactin (also known as mevastatin), simvastatin, lovastatin and pravastatin.
  • the compounds could be new members of the statin family or they could be intermediates in the statin metabolic pathway.
  • the isolated compounds comprise statins.
  • the isolated compounds have similar UV-spectra as defined above, and their alkyl phenone retention index (Rl), as defined earlier, is comprised in the range from 887-967 as shown in the example.
  • Rl alkyl phenone retention index
  • the isolated compounds can be characterized by having a Rl selected from the ranges 891-904, 946-959, or 960-964.
  • the compounds according to the present invention are also highly fluorescent when using an excitation wavelength of 230 nm and an emission wavelength of 450 nm.
  • the compound of the invention was purified and NMR- spectra were recorded at 600.13 MHz for 1 H and 150.92 MHz for 13 C.
  • the chemical shifts are given relative to DMSO (Dimethyl Sulfoxide), 2.5 ppm for 1 H and 39.5 ppm for 13 C.
  • the NMR- data resulted in a chemical structure of formula (IV) as shown below.
  • Statan A is the compound of formula (IV) wherein X is the group shown in formula (II).
  • Statan A may advantageously be used according to the invention as intermediate for preparing other statans of the invention as depicted in formula (I).
  • R ⁇ represents OH, C 6 H 5 COO, R 6 COO and R 6 represents C T -C S alkyl
  • R 2-4 represents H, C 1 -C 5 alkyl, or C C 5 acyl
  • R 5 represents H, CH 3
  • X represents a compound of formula (II) or (III)
  • R 6 can be a branched or straight alkyl.
  • the compounds of formula (I) can be produced from the compound of formula (IV).
  • R 2 , R 3 , t can be substituted with C Cs alkyl or C C 5 acyl by a Fridel Kraft alkylation or acylation as described in example 8.
  • R ⁇ representing R 6 COO where R 6 represents C C 5 alkyl can be produced from a compound of formula (IV) by esterification of the R position as described in examples 5 and 6.
  • Ri is 2-methylbuturyl or 2-dimethylbutyryl or C 6 H 5 COO (or PhCOO). Benzylation of Statan A at R 1 is described in example 7.
  • esterification may be carried out by a process employing an immobilized lipase enzyme in a nonaqueous system.
  • An example of such a lipase enzyme is Candida cylindracea C (Type VII from Sigma Chemical Co.).
  • the process is described in US 5,420,024 and furthermore lists microbes which make the enzyme with the corresponding deposit numbers (see table 1 in US5,420,024), the content of which is incorporated by reference.
  • Compounds which may be prepared include those wherein R is R 6 is ethyl, n-propyl, 2-butyl or 2-methyl-2-butyl.
  • Statan A can in a further embodiment be used for ether formation, e.g. the formation of statan butyl ether as described in example 9.
  • R 5 can be substituted with methyl using any method know in the art, e.g., as described in TETRAB, Tetrahedron, 44, 18, 1988: 5745-5760 or J. Org. Chem, 48, 17, 1983: 2814-2820 or shown in examples 11 and 12.
  • the invention includes all optical isomers of compounds of the present invention, some of which are optically active, and also their mixtures including racemic mixtures thereof.
  • optical isomers of compounds of the present invention include all optical isomers of compounds of the present invention, some of which are optically active, and also their mixtures including racemic mixtures thereof.
  • tautomeric forms of the compounds of the present invention as well as metabolites or prodrugs.
  • the compounds of the present invention are found in compactin producing species. Accordingly in one embodiment of the present invention the isolated compounds described above are derived from Penicillium species, including preferably psychrophilic or psychrotolerant species of Penicillium. In another embodiment the said Penicillium sp is P. solitum.
  • a suitable P.solitum strain for providing the compounds of the present invention could in a further embodiment be P.solitum CBS 147.86 (deposited at Centraalbureau voor Schimmelcultures).
  • the below deposited Penicilium species are specifically contemplated, i.e., P. neocommune, preferably strain CBS 111 ,239; P. novoniwotense, preferably strain CBS 111 ,240; P. landeri, preferably strain CBS 111 ,241 ; P. lanosum, preferably strain CBS 11 1 ,243; and P. pinicola, preferably CBS 111 ,244.
  • statins have been demonstrated to have several beneficial therapeutic effects as e.g. lipid lowering agents used for lowering serum cholesterol levels, promotion of bone formation for use in osteoporosis, immunosuppessing effects, and new and improved pleiotropic effect.
  • a further aspect of the present invention therefore relates to a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to the invention, or a pharmaceutically acceptable salt or metabolite or prodrug thereof, and a pharmaceutical acceptable carrier.
  • a "metabolite" of a compound disclosed herein is an active derivative of a compound disclosed herein which is produced when the compound is metabolized. Metabolites of compounds disclosed herein can be identified either by administration of a compound to a host and an analysis of blood samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the incubant.
  • a “prodrug” is a compound that either is converted into a compound disclosed in the application in vivo or has the same active metabolite as a compound disclosed in this application.
  • Such prodrug form could e.g. be a physiologically-hydrolysable and acceptable ester meaning an ester in which the hydroxyl group is esterified and which is hydrolysable under physiological conditions to yield an acid which is itself physiologically tolerable, at dosages to be administered.
  • the term is thus to be understood as defining regular prodrug forms.
  • esters include for example acetates, as well as benzoates of the compounds of the invention.
  • the salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts or optionally alkylated ammonium salts, such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, trifluoroacetic, trichloroacetic, oxalic, maleic, pyruvic, malonic, succinic, citric, tartaric, fumaric, mandelic, benzoic, cinnamic, methane- sulfonic, ethane sulfonic, picric and the like, and include acids related to the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, or lithium, sodium, potassium, magnesium and the like.
  • the pharmaceutical composition of the invention may comprise at least one compound according to the invention combined with one or more other pharmacologically active compounds.
  • the pharmaceutical composition further comprises acetyl salicylic acid.
  • the invention relates to a method for the production of a compound of formula (V) or (I).
  • Formula (V) is formula (I), where R ⁇ represents OH, R 2-4 represents H, R 5 represents CH 3 , and X represents a compound of formula (II) or (III).
  • the present invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the present invention or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutically acceptable carrier or diluent.
  • compositions comprising a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy, 19 th Ed., 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions or suspensions.
  • compositions include a compound of the present invention or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in form of a capsule, sachet, paper or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi- solid, or liquid material, which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or coloring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral e.g. rectal, depot, subcutaneous, intramuscular or intranasal, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid earner is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • the compounds of the invention may be administered to a mammal, especially a human, in need of such reducing or lowering of the intake of fat food.
  • mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, in an effective amount.
  • compositions containing a compound according to the invention may be administered one or more times per day or week, conveniently administered at mealtimes.
  • An effective amount of such a pharmaceutical composition is the amount that provides a clinically significant effect against consumption of fat food. Such amounts will depend, in part, on the particular condition to be treated, age, weight, and general health of the patient, and other factors evident to those skilled in the art.
  • the structure of the compounds according to the invention resembles the structure of naturally occurring statins and a further embodiment of the invention thus relates to the use of the said compounds for the production of a statin.
  • the said statin comprises in another embodiment compactin, simvastatin, lovastatin, and pravastatin.
  • the present invention relates to a use of the compounds of the invention as a medicament.
  • the present invention relates to a use of the compounds of the invention for the manufacture of a medicament for the treatment of hypercholesterolemia or osteoporosis or as an immunosuppressor.
  • a further aspect of the present invention relates to a method of reducing the level of low-density lipoprotein cholesterol (LDL-C) in a human or animal by administering an effective amount of at least one compound according to the invention.
  • the invention relates to a use of solstatin (S ⁇ rensen et al., 1999, Phytochemistry 51 :1027-1029) for the preparation of a medicament and in a particular embodiment for the use of the said medicament for treatment of hypercholesterolemia or osteoporosis or as an immunosuppressor.
  • the compounds of the invention can be produced in any conventional way known to the skilled person by providing a suitable host organism comprising the compound of the invention and growing the said organism in a suitable culture medium under conditions promoting the production of the said compound(s) and recovering the compound(s) from the host organism or culture medium.
  • the culture broth comprising statans after growing the organisms of the invention can be use for the preparation of a pharmaceutical composition.
  • the said host organism is in one embodiment a fungus.
  • the said host organism is a Penicillium sp. like e.g. a P. solitum, including P. solitum CBS 147.86 (redeposited as Penicillium solitum CBS 111.242 (NN049656) on 29 November 2002) or one of the following deposited strains: Deposit NZ Number Accession Number Date of Deposit
  • Penicillium sp. NN049654 CBS 111240 29 November 2002
  • Penicillium sp. NN049655 CBS 111241 29 November 2002
  • strains have been deposited under conditions that assure that access to the culture will be available during the pendency of this patent application.
  • Strain CBS 111 ,240 may be referred to as Penicillium novoniwotense Frisvad (sp.nov) and originates from Faeroe Islands, Denmark.
  • Strain CBS 111 ,241 may be refer to as Penicillium landeri Frisvad (sp.nov) and originates from Wind River Range, Wyoming, US.
  • Strain CBS 11 1 ,242 (NN049656) is of the species Penicillium solitum and has been isolated from apple, Denmark.
  • Strain CBS 111 ,243 (NN049657) is of the species Penicillium lanosum and has been isolated from soil under spruce tree, Brandy Wine Falls, British Colombia, Canada. Strain CBS 111 ,244 (NN049658) may be referred to a Penicillium pinicola Frisvad
  • HMGR 3-hydroxy-3-methylglutaryl coenzyme A reductase
  • the compounds of the present invention can be analyzed for their effectiveness as HMGR inhibitors by any method that can directly or indirectly measure the level of LDL-cholesterol in the subject.
  • One such test could be the COBAS INTEGRA® HDL-Cholesterol Direct (Roche Diagnostics).
  • Nielsen et al. (Pharmacology & Toxicology, 1993, 72: 148-151 ) and Holm et al. (Arteriosclerosis, Thrombosis, and Vascular Biology, 1997, 17: 2264-2272) describes methods for the determination of various forms of cholesterol, both references are hereby incorporated by reference.
  • the fungus Penicillium solitum CBS 147.86 (redeposited as CBS 111.242) is inoculated from a resuspension of a preserved freeze-dried spore and inoculated on malt extract agar [according to Blakeslee] (See Samson, R.A., Hoekstra, E.S., Frisvad, J.C. and Filtenborg, O. (eds.) Introduction to food- and airborne fungi. 6th edition., 2000, 378-382) and incubated at 20°C for 1 week. The conidia are suspended in peptone (0.1%) in water to produce a suspension of approximately 10.000 conidia pr ml.
  • the organic phase is filtered using a hydrophobic filter and the organic solvents evaporated in a rotary evaporator under vacuum at 40°C.
  • the remaining dry extract is re-dissolved in 1 ml methanol, filtered and injected into the HPLC-DAD system (Agilent).
  • the HPLC-DAD system should be connected with an effective fluorescence detector in order to confirm the presence of statans. All compounds should be analyzed using the HPLC-DAD system of Frisvad and Thrane (Frisvad and Thrane, J. Chromatogr.(1987) 404:195-214; Frisvad and Thrane In Betina, V. (Ed.)Chromatography of mocotoxins: techniques and applications J.
  • statin-like compounds have the following properties:
  • Statans Statan A: Rl (alkylphenone retention index) average 953 (range 946-959), Statan Af. Rl average 961 (range 960-964), statan B: Rl average 898 (range 891-904) (as compared to compactin Rl average 1108).
  • statans are highly fluorescing when excitation is performed at 230 nm and using an emission wavelength of 450 nm. Few other secondary metabolites from fungi fluoresce at these conditions (an example is ochratoxin A and B, but these have completely different UV spectra and retention indices).
  • the isolate CBS 147.86 (redeposited as CBS 111.242) was cultured for 2 weeks in the dark at 20°C as three point mass inoculations on 1000 Petri dishes (9 cm) on about 20 liter of yeast extract sucrose agar (YES) (yeast extract 20 gr, sucrose 150 g, agar 20 g, distilled water).
  • yeast extract sucrose agar YES
  • the content of the Petri dishes were extracted twice with 10 liter of EtOAC to give ca. 25 g of crude extract which was partitioned between a total of 1 liter of heptane and 1 liter of 90 % MeOH in order to remove lipids and apolar compounds.
  • the MeOH fraction was diluted to 60 % and extracted with a total of 1 liter of CH 2 CI 2 to give a total of 8 g of Statan A (formula IV) rich extract.
  • This extract was then coated onto 8 g of Celite and divided into three portions which subsequently were separated by vacuum liquid chromatography on a C 18 SPE column (10 g) into four fractions using 100 ml of H 2 O/MeOH in the following amounts A:(75:25), B:(50:50), C:(25:75) and D:(0:100).
  • the C fraction (4.6 g) rich in Statan A was further separated on a Sephadex LH20 column (25 x 900 mm) using MeOH at 1 mL/min to give 8 fractions (CA-CF).
  • CE fraction (96 mg) was subjected to HPLC separation on a Waters Prep Nova-Pak C18 cartridge (25 x 100 mm, 6 micro m) using H 2 O/CH 3 CN (65:35) as mobile phase to give 30 mg of pure Statan A.
  • a petri dish with PDA potato dextrose agar was inoculated (at 3-points) with fungal isolate P. solitum CBS 147.86 (redeposited as CBS 111.242) and incubated at 25 °C for 7 days.
  • Conidia were harvested by addition of 5 mL sterile H 2 O, holding 0.1 % Tween per plate.
  • the conidia were released from the mycelium by gentle scraping with pipette tip.
  • the resulting suspension of conidia were poooled from two plates at a time and added to a flask with a total volume of 100 mL H 2 O (0.1 % Tween, final concentration).
  • a fed batch culture condition in 2L scale was used.
  • Composition of medium 20 g/L yeast extract (Difco), 20 g/L sucrose, 18 mg/L ZnSO 4 -7H 2 O, 8 mg/L CuSO 4 -5H 2 O, 1 ml/L Pluronic (antifoam), pH ajusted to 5,0 prior to sterilization.
  • Feed 500 g/L sucrose, 2 ml/L Pluronic (antifoam).
  • the fermentation tank was inoculated by adding 2 mL of the spore suspension (described above).
  • Feed start 36 h after inoculation, feed rate 2.5 g/IJh.
  • pH control >4 (10% NaOH) and ⁇ 6 (10% H 3 PO 4 ).
  • Airflow 1 L/min.
  • HPLC conditions Column: Agilent, Hypersil with BDS-C18, 3 urn (mymeter), 4.0 x 100 mm;
  • NMR spectra of statans were recorded in 5 mm tubes at 600.13 MHz for 1 H and at 150.92 MHz for 13 C and at 300 K, using DMSO-cf 6 , on a Bruker DRX 600 according to Larsen et al. ,2001, (J Agricult and Food Chem 49: 5081-5084).
  • the 13 C and the C.H-COSY spectra revealed the presence of one methyl, four methylene, and two methine groups, together with 5 aromatic protons, two hydroxy protons (9.95 and 5.20 ppm), 5 quartemary aromatic carbon atoms and finally a carboxy group at 170.2 indicating an ester or lactone.
  • Phenolic and naphtolic ketones are produced by the rearrangement of their phenolic or naphtolic esters in the presence of anhydrous aluminium chloride.
  • the cholesterol-lowering effect of Statan A was compared against a control in male White rabbits (purchased from Hvidesten, DK).
  • the rabbits were housed in individual stainless steel cages with free access to water.
  • the rabbits were divided into groups with similar baseline values of plasma cholesterol, which groups received:
  • the rabbits were treated for 3 days. All animals were fed daily with 100 g of a standard rabbit diet (Altromin, Germany) containing 1 % cholesterol. All test drugs were added to the diet. Remaining food were weighed.
  • Blood samples for cholesterol determination were drawn at baseline and at the three following days. Blood samples were taken from the marginal ear vein and the cholesterol determination was done the same day by enzymatic colorimetric methods, using a commercially available kit (CHOD-PAP, Roche), on a COBAS MIRA auto-analyzer (Roche, Basle, CH).
  • the rabbits are selected as hyper-, normo- or hyporesponsive to dietary cholesterol.
  • the hyposensitive rabbits are fed with 1 % cholesterol chow 5 days before administration of the test drug. Thereafter the rabbits are fed daily for 3 days with the cholesterol-enriched (1 %) chow containing the test drugs.

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Abstract

L'invention concerne des composés présentant des structures ressemblant à des statines naturelles isolées à partir de Penicillium sp. En particulier, l'invention concerne des composés isolés présentant des spectres d'absorption relatif à UV max comme mesurés par HPLC-DAD, de 222-224 nm (100 %), épaulement de 229-234 nm (84-89 %), épaulement de 290 nm (13 %), 303-305 nm (14-15 %), épaulement de 318-320 nm (9-11 %), 331-333 nm (7,5-8,5%) et de formule (IV), ainsi que des compositions pharmaceutiques les contenant.
EP02781169A 2001-12-03 2002-12-03 Composes de type statine Withdrawn EP1453819A2 (fr)

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